This invention relates to the preparation of calcium/oxyanion-containing particles for use in medical diagnostic imaging, such as magnetic resonance imaging ("MRI"), ultrasound, and X-ray. In particular, the present invention is directed to the use of a microfluidizer for the preparation of calcium/oxyanion-containing particles having a uniform small (&lt;5 .mu.m) size distribution. The present invention also includes the use of tangential flow filtration for particle purification.
The use of contrast agents in diagnostic medicine is rapidly growing. In X-ray diagnostics, for example, increased contrast of internal organs, such as the kidneys, the urinary tract, the digestive tract, the vascular system of the heart (angiography), etc., is obtained by administering a contrast agent which is substantially radiopaque. In conventional proton MRI diagnostics, increased contrast of internal organs and tissues may be obtained by administering compositions containing paramagnetic metal species which increase the relaxivity of surrounding protons. In ultrasound diagnostics, improved contrast is obtained by administering compositions having acoustic impedances different than that of blood and other tissues.
Often it is desirable to image or treat a specific organ or tissue. Effective organ- or tissue-specific diagnostic agents accumulate in the organ or tissue of interest. Copending U.S. Pat. No. 5,344,640, filed Sep. 22, 1992, titled "Treated Apatite Particles for Medical Diagnostic Imaging," which is incorporated herein by reference, discloses the preparation and use of apatite particles for medical diagnostic imaging. This patent application also describes methods for preparing apatite particles which provide organ- or tissue-specific contrast. By carefully controlling the particle size and route of administration, organ specific imaging of the liver, spleen, gastrointestinal tract, or blood pool is obtained.
In general, the apatite particles are prepared by modifying conventional methods for preparing hydroxyapatite (sometimes referred to as "hydroxylapatite"). For example, stoichiometric hydroxyapatite, Ca.sub.10 (OH).sub.2 (PO.sub.4).sub.6, is prepared by adding an ammonium phosphate solution to a solution of calcium/ammonium hydroxide. Useful apatite particles may also be prepared by replacing calcium with paramagnetic metal ions. Other apatite derivatives are prepared by replacing the OH.sup.31 with simple anions, including F.sup.-, Br.sup.-, I.sup.-, or 1/2[CO.sub.3.sup.2- .
Various techniques for controlling the particle size for certain calcium phosphate-containing compounds (apatites) are disclosed in copending U.S. Pat. No. 5,344,640. For example, slower addition rates (introduction of the precipitating anion or cation), faster stirring, higher reaction temperatures, and lower concentrations generally result in smaller particles. In addition, sonication during precipitation, turbulent flow or impingement mixers, homogenization, and pH modification may be used to control particle size. Other means, such as computer controlled autoburets, peristaltic pumps, and syringes, may be used to control the release of precipitating ions to produce smaller particles.
Due to the small size and nature of apatite particles, they tend to aggregate. Particle aggregation may be inhibited by coating the particles with coating agents, while agglomerated particles may be disrupted by mechanical or chemical means and then coated with a coating agent having an affinity for the apatite.
One preferred method of obtaining small, uniformly sized, manganese-doped apatite particles is to dropwise add a degassed solution of (NH.sub.4).sub.2 HPO.sub.4 and NH.sub.4 OH into a rapidly stirring degassed solution of Ca(NO.sub.3).sub.2 .cndot.4H.sub.2 O and Mn (NO.sub.3).sub.2 .cndot.6H.sub.2 O. The resulting apatite particles are then reacted with a solution of 1-hydroxyethane-1,1-diphosphonic acid (HEDP). The smaller particles are separated from larger particles by repeated centrifuging and collection of the supernatant. The particles are then washed to remove base and salts by centrifuging at a higher rpm, discarding the supernatant, resuspending the solid pellet in water, and recentrifuging.
Although the foregoing procedure produces small-sized apatite particles having good size distribution and good medical diagnostic imaging properties, the repeated centrifuging, decanting, and washing causes the process to be tedious and time-consuming. It, therefore, would be a significant advancement in the art to provide an improved method for rapidly preparing calcium/oxyanion-containing particles for medical diagnostic applications having a controlled particle size distribution and good yield.
Such methods for preparing calcium/oxyanion-containing particles are disclosed and claimed herein.